3-(1,3-dialkoxy-, and 1-hydroxy-3-alkoxy-9-oxo - 4-acridanyl)propionates as intermediates for acronycine and related compounds

ABSTRACT

THE TOTAL SYNTHESIS OF ACRONYCINE AND RELATED COMPOUNDS FROM READILY AVAILABLE STARTING MATERIALS IS DESCRIBED, AS ARE VARIOUS CLASSES OF INTERMEDIATES USEFUL IN THE SYNTHESIS.

3 766 187 3-(1,3-DIALKOXY-, ANI) 1- HYDROXY-3-ALKOXY-9- X04-ACRIDANYL)PROPIONATES AS INTER- MEDIATES FOR ACRONYOINE AND RELATED3,766,187 Patented Oct. 16, 1973 In addition, Govindachari et al.isolated the related compounds, noracronycine, des-N-methylacronycineand des-N-methylnoracronycine, from the root bark of Glycosmispentaphylla. Finally, the synthesis of acrony- COMPOUNDS 5 cine fromnoracronycine was described in Aust. J. Sci.

James R. Beck, Indianapolis, Ind., assignor to Eli LillyRes-21516220949)- and Company, Indianapolis, Recently, it was found bySvoboda and co-workers [1. N0 Drawing. Original application July 17,1967, Ser. No. Pharm- 758 and Lloydla 29, 206 653,667, now Patent No.3,624,087. Divided and this that acronycme had an extremely powerfulanti-tumor application July 6, 1971, Ser. No. 128,529 action againsttransplanted tumors in mice, particularly (307d 37/ 20 against Shionogicarcinoma, C-1498 myelogenous R 3 Clalms leukemia, Mecca lymphosarcomaand X-55 63 plasma cell myeloma. ABSTRACT OF THE DISCLOSURE SUMMARY Thetotal synthesis of acronycine and related com- This invention provides amethod of synthesizing poimds from readily available Starting m aterialsis acronycine which comprises first :cy-clizing 'N-(B-haloproscribed, asare various classes of intermediates useful [[1 pionyl) 3,s di loweralkoxyaniline to yield a s,7 di lower the synthesis.alkoxy-3,4-dihydrocarbostyril, reaction of which with an o-halobenzoicacid under Ullmann conditions yields a l- CROSS-REFERENCE TO RELATED 5ypy 5,7 i 1 w -a y- ,ty APPLICATION carbostyril. Treatment of the lattercompound with a conf densing agent such as polyphosphoric acid yields amixture app Ion lvlslon O co'pen mg app of a3-(1,3-dialkoxy-9-oxo-4-acr1danyl)propionic acid and j filed July 1967now the corresponding inner lactam. Esterification of this mixture withan alkanol yields a lower alkyl 3-(l,3-dialkoxy BACKGROUND OF THEINVENTION 9-oxo-4-acridanyl)propionate. This latter COlTifiOilIld(iSnext selectively dealkylated to give a lower a y 3- Wiliamintensities;sealants 4 Aust J Res 2A 423 (1949)] i chemistry ofalkylation of which with an alkyl lithium or lower-alkyl Grignardreagent yields a 1-hydroxy-3-lower-alkoxy-4-(3- ment of this lattercompoun wit aci yie s a yes? iriiz iiaizsiu iaisnaiiia -ce]acri anone.and P T g ig gf f f 3245 (1966) that In the above reaction when there isno substituent acronycme a e o owmg S we present in the o-halobenzoicacid and where the alkylating agent is methyllithium or methylmagnesiumbromide, the resulting compound is N-desmethylnordihydroacronycine. 40N-methylation of N-desmethylnordihydroacronycine followed by selectivedehydrogenation using dichlorodicyanoquinone (DDQ) yields noracronycinedirectly. 0-

I alkylation of noracronycine yields acronycine. The above synthesis canbe visualized in Reaction Scheme I which follows: CH3 REACTION SCHEME IO-alk O-ulk O-alk ooorr COOH salt R CuX- R HN O-alk O-alk inert O-alksolvent \N/ HN 0: -C2H4X l I II III IV olylphosphorlc acid 0 O-alk0-1111: 0 O-alk II I I I II HCl R"OH R R R N 0-a1k g O-alk N -O-alk HHzCHz-C O O R" Hr-CHz-COOH U VII VI V f) 011 (HI DD Q R 4- R 1 I't' alkalk alk XII R =H X R H XIII R'=CH3, 07H: 01' CnHsCHz XIV R CH:(noracronyelne) alk OH:

alkylatlon O O-alk XI R =CHa, C2115 01' oHa 2 V R =H(acronyclne) R andalk=OHa In the above reaction scheme, X and X can be chlorine, bromineor iodine and alk is a lower-alkyl group having from 1 to 4 carbonatoms, either straight chained or branched chained, for example, methyl,ethyl, n-propyl, isopropyl, n-butyl, iso-butyl and the like; R can behydrogen, halogen, nitro, trifluoromethyl, alk, or O-alk; R is hydrogen,methyl, ethyl, benzyl; and R" is methyl or ethyl.

As previously mentioned, the first step of our novel multi-stepsynthesis of acronycine involves the cyclization of anN-(B-halopropionyl)-3,5-di-lower-alkoxyaniline (I) to a.5,7-di-lower-alkoxy-3,4-dihydrocarbostyril (II). The cyclization iscarried out by the fusion of (I) with a mild, essentially anhydrous,Friedel-Crafts catalyst such as zinc chloride, zinc bromide, stannouschloride, antimony trichloride and the like, optionally in the presenceof an alkali metal halide. The fusion of (I) in the presence of one ofthe aforementioned heavy metal catalysts is carried out at a temperatureof about 50 C. to about 250 C., no solvent being required. In carryingout the cyclization of (I), we prefer to use zinc chloride in arelatively anhydrous state in combination with an alkali metal halide,such as sodium chloride, at a temperature of about 150 C. althoughhigher or lower temperatures are fully operative. Addition of two partsof sodium chloride to one part of the zinc salt has an advantageouseffect on the yield of (II).

In the second step, the 3,4dihydrocarbostyril (II) is reacted with ano-halobenzoic acid (III) in the presence of cuprous iodide or othercuprous salt to yield the 1-(2- carboxyphenyl)-3,4dihydrocarbostyril(IV). The reaction conditions are typically those used in the Ullmannreaction. The reaction is carried out in an inert solvent, such asnitrobenzene, in the presence of a hydrogen halide acceptor, such as,potassium carbonate, sodium carbonate and the like at a temperature ofabout 100 C. to about ldealkylate O 0 H OH I I alk-Ll ethereal solvent BR N -O -ulk N O -alk alk I-I;GII;C O 0 It" 112-011;

OH VIII IX lucid optional alkylatlon 250 C. We prefer to carry out thereaction of (II) with (III) where X is iodo in the presence of cuprousiodide in nitrobenzene at a temperature of about 150 C. for 24 hours.

The 1-(Z-carboxyphenyl)-3,4-dihydrocarbostyril (IV) produced in theabove reaction is then cyclized by treatment with polyphosphoric acid orother equivalent condensing agent at a temperature of about 50 C. toabout 150 C. to yield a mixture consisting of a1,3-di-loweralkoxy-9-oxo-4-acridanylpropionic acid (VI) and thecorresponding inner lactam, 2,3-dihydro-4,6-di-lower-alkoxy-1H,7H-pyrido-[3,2,l-de]acridine-l,7-dione (V) where alk and R are asdefined above. This cyclization is preferably carried out at atemperature of about (3., though high er or lower reaction temperaturesare fully operative.

The mixing comprising (V) and (VI) is next treated with 1 N methanolicor ethanolic hydrogen chloride at reflux temperature to yield theoptionally substituted methyl or ethyl 9-oxo-4-acridanylpropionate(VII), where R, R" and alk are as defined above. During this reaction,the 2,3-dihydro-4,6-di-lower-alkoxy-1H,7H-pyrido- [3,2,1 de]acridine-l,7-dione (V) component of the above mixture is converted to(VII) by an alcoholysis reaction, and the acridanylpropionic acid (VI)component of the mixture is concurrently converted to (VII) byesterification. Thus, the separation of the mixture of (V) and (V1) isobviated by this one step methanolysis-esterification reaction.

The 9-oxo-4-acridanylpropionate (VII) is then selectively dealkylated toyield a 1-hydroxy-3-methoxy-9-oxo- 4-acridanylpropionate (VIII), basedon the procedure of F. M. Dean et 211., Tetrahedron Letters, 4153-4159(1966), which procedure utilizes boron trichloride in an inert solventas the dealkylating agent. Alternatively, this selective dealkylation ofthe l-alkoxy group of (VII) to obtain (VIII) has been carried out with aGrignard reagent in an ether-pyridine solvent system at a temperature ofabout 60 C. In this alternate procedure, the preferred Grignard reagent,selected from among the lower alkylmagnesium bromides or iodides--forexample methylmagnesium iodide in etheris first mixed with pyridine.Next a pyridine solution of (VII) is added. The reaction mixture is thenheated for about four hours at a temperature of about 60 C. to yield(VIII). We prefer, however, to carry out the selective demethylation of(VII) by the aforementioned procedure based upon that of F. M. Dean etal., loc. cit. According to this procedure, (VII) is dissolved inmethylene chloride and the solution treated with excess gaseous borontrichloride at a temperature of about 0 C. The reaction is carried tocompletion by allowing the mixture to remain at ambient temperature for30 minutes. Excellent yields of the l-hydroxy-3-alkoxy-9-oxo-4-acridanylpropionate (VIII) are thus obtained.

The monohydroxy compound (VIII) is next reacted with a loweralkyllithium where lower alkyl is the same as defined above, in anethereal solvent such as diethyl ether, tetrahydrofuran or diethyleneglycol dimethyl ether, to yield a tertiary carbinol (IX). In thisreaction, the alkyllithium converts the propionate ester group to atertiary alcohol. The reaction is carried out at a temperature in therange -70 C. to 0 C. in an inert atmosphere of a gas such as nitrogen.We prefer to carry out the preparation of (IX) in the solventtetrahydrofuran at a temperature of about C. with a reaction time ofabout minutes to obtain maximal yields of the tertiary carbinol.

Upon treatment of the tertiary carbinol (IX) with 48 percent hydrobromicacid in glacial acetic acid at or near reflux temperature cyclizationoccurs involving the 3-alkoxy substituent and the tertiary hydroxylgroup of (IX) to yield the 3,3-di-lower-alkyl-2,3-dihydro-7(12H) 1H-pyrano[2,3-c]acridinone (X). Preferably, however, the above cyclizationis carried out by fusing ('IX) wtih pyridine hydrochloride at atemperature of about 200 C. The reaction is usually complete after aboutfour hours. (X) is obtained in a purified state by column chromatographyover silica gel or similar material in a benzeneethyl acetate solventcombination. Alternatively, we find it advantageous in carrying out oursynthesis to convert (X) in the crude state to the more easilyisolatable (XI) by the N-alkylation of (X) with a methyl halide, anethyl halide or a benzyl halide in refluxing acetone in the presence ofpotassium carbonate. The above cyclization reac tion whereby an alkoxygroup undergoes cleavage, followed by intramolecular cyclization with atertiary carbinol, is unique and indeed is a key step in the totalsynthesis of acronycine and related compounds. The product of the abovealkylation (X) where R is H is classified as aN-desmethylnordihydroacronycine but when R is other than hydrogen, thecompound is classified as a dihydronoracronycine. Treatment of eitherthe normal or the N-desmethyl derivative with a quinone having a highstandard oxidation potential (E preferably in the neighborhood of 1.0volt in an inert solvent, yields a 6-hydroxy- 3,3-di-lower-alkyl 1,2dihydro-pyrano-[2,3-c] acridinone (XIII). We prefer to carry out thisdehydrogenation with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) inrefluxing toluene over a 1-3 hour period. This unique method for theintroduction of the carbon to carbon double bond in the dihydropyranylring of (X) or (XI) affords surprisingly high yields.

In carrying out the series of reactions depicted in Reaction Scheme I,where R is H, R' and alk are methyl, dihydronoracronycine was obtained(XI). Oxidation of dihydronoracronycine with DDQ as described aboveafforded noracronycine identical in physical and chemical properties tothe natural noracronycine reported by R. D. Brown, L. J. Drummond, F. H.Lahey and W. C. Thomas, Australian J. Sci. Research A2, 423 (1949).Methylation of noracronycine by the method of R. D. Brown et al., 10c.cit. yielded acronycine.

The above synthetic procedure when carried out with compounds in whichalk and R are methyl and R is hydrogen yields acronycine which, as hasbeen previously stated, has been found to be extremely useful in thetreatment of experimental tumors in mice and is a potential addition tothe armamentarium of anti-neoplastic drugs. The process of thisinvention is also useful for preparing compounds related to acronycinein which alk, R and R are other than as specified as acronycine. Thesecompounds, as well as compounds related to noracronycine [(X lIl) whereR is other than hydrogen and alk is methyl] have an effect on thecentral nervous system which is generally a stimulating action, althoughcertain of the compounds have sedative effects. Compounds correspond ingto Formulas II, IV, V, VI, VII, VIII, IX and X all represent novelstructures and are all useful as intermediates for the preparation ofacronycine and related compounds as represented by XVI.

Further aspects and equivalents of the present invention will becomeobvious to one skilled in the art. The following examples further definethe present invention but are not intended in any way to limit the scopeof the invention.

EXAMPLE 1 5,7-dimethoxy-3,4-dihydrocarbostyril One hundred thirty gramsof 3,5-dimethoxy-N-( 3- bromopropionyl) aniline and g. of zinc chloride(previously dried for 2 hours at C.) were fused at 150 C. for 30minutes. The reaction mixture was allowed to cool to room temperatureand the 5,7-dimethoxy-3,4-dihydrocarbostyril formed in the abovereaction was extracted therefrom with 400 ml. of ethyl acetate. Theextract was washed successively with 400 ml. of 3 N hydrochloric acid,with a saturated solution of sodium bicarbonate and with a saturatedsolution of sodium chloride. The extract was separated and dried, andthe solvent removed therefrom to yield 17 g. of5,7-dimethoxy-3,4-dihydrocarbostyril melting at about 192-194 C. afterrecrystallization from methyl alcohol.

Analysis.Calculated (percent): C, 63.75. H, 6.32; N, 6.76. Found(percent): C, 63.83; H, 6.64; N, 6.76.

EXAMPLE 2 5,7-dimethoxy-3,4-dihydrocarbostyril (zinc chloridesodiumchloride method) One hundred forty grams of3,5-dimethoxy-N-(fibromopropionyl) aniline were added rapidly to amixture, previously dried at C. for 2.5 hours, consisting of 70 g. ofzinc chloride and 140 g. of sodium chloride at a temperature of about155 C. The reaction mixture was maintained at a temperature of about 155C. for 20 minutes, cooled to room temperature, and5,7-dimethoxy-3,4-dihydrocarbostyril formed in the above reaction wasextracted therefrom with 500 ml. of ethyl acetate. The extract waswashed successively with 400 ml. of 3 N hydrochloric acid, water, asaturated solution of sodium bicarbonate, and a saturated solution ofsodium chloride. The extract was separated and dried and the solventevaporated therefrom in vacuo. The resulting residue yielded 16.9 g. of5,7-dimethoxy-3,4-dihydrocarbostyril melting at about 192-194 C. afterrecrystallization from methanol. The mother liquor was evaporated invacuo to yield 100 g. of an oil consisting of partially demethylatedproduct. The oil was treated with a mixture of 300 ml. of methyl iodideand 240 g. of potassium carbonate in one liter of acetone at refluxtemperature for 72 hours. The reaction was cooled, filtered, and thesolvent evaporated in vacuo. An additional 11.7 g. of5,7-dimethoxy-3,4-dihydrocarbostyril melting at about 195 196 C. afterrecrystallization from methanol were obtained from the residue.

Analysis.-Calculated (percent): C, 63.75; H, 6.32; N, 6.76. Found(percent): C, 63.83; H, 6.64; N, 6.76.

7 EXAMPLE 3 1- (Z-carboxyphenyl)-5,7-dimethoxy-3,4- dihydrocarbostyrilEight grams of 5,7-dimethoxy-3,4-dihydrocarbostyril and 19.8 g. of2-iodobenzoic acid were reacted together in the presence of 0.5 g. ofcuprous iodide, 0.2 g. of cupric acetate monohydrate, 16 g. of potassiumcarbonate and 175 ml. of nitrobenzene. The reaction mixture wasmaintained at a temperature of about 150 C. for 24 hours with continualstirring, and was then steam distilled to remove the nitrobenzene. Theaqueous mixture was filtered and acidified.1-(Z-carboxyphenyl)-5,7-dimethoxy 3,4-dihydrocarbostyril, formed in theabove reaction, was extracted therefrom with 400 ml. of ethyl acetate.The organic extract was washed with a saturated solution of sodiumchloride which was discarded. The carbostyril was extracted from theorganic layer with a saturated aqueous solution of sodium bicarbonate.The sodium bicarbonate extract was acidified and the productre-extracted with ethyl acetate. The ethyl acetate extract was dried,and the ethyl acetate removed therefrom by evaporation in vacuo. Threegrams of l-(2-carboxyphenyl)- 5,7-dimethoxy-3,4-dihydrocarbostyril wereobtained from the resulting residue melting at about 223 225 C. afterrecrystallization from methyl alcohol.

Analysis.Calculated (percent): C, 66.05; H, 5.24; N, 4.28. Found(percent): C, 65.83; H, 5.37; N, 4.22.

EXAMPLE 4 Methyl 3-( 1,3-dimethoxy-9-oxo-4-acridanyl)-propionate Fourgrams of l (2 carboxyphenyl)-5,7-dimethoxy- 3,4-dihydrocarbostyrilprepared as in Example 3, and 160 ml. of polyphosphoric acid were mixedtogether and the mixture heated at about 100 C. for 1.5 hours. Thereaction mixture was poured over 400 g. of crushed ice, yielding a solidprecipitate which was filtered and dried by azeotropic distillation. Thedried precipitate Was dissolved in 100 ml. of 1 N methanolic hydrogenchloride and the solution refluxed for 2.5 hours. The solvent wasremoved therefrom by evaporation in vacuo to yield 3.7 g. of a residueconsisting essentially of methyl3-(1,3-dimethoxy-9-oxo-4-acridanyl)-propionate. Suspension of theresidue in 400 ml. of a saturated sodium bicarbonate solution, followedby separation and recrystallization of the thus obtained product, gavepurified methyl 3-(1,3-dimethoxy-9-oxo-4-acridanyl)-propionate meltingat about 244-245 C.

Analysis.Calculated (percent): C, 66.85; H, 5.61; N, 4.10. Found(percent): C, 66.81; H, 5.64; N, 4.07.

EXAMPLE 5 Methyl 3-( 1-hydroxy-3-methoxy-9-oxo-4-acridanyl)- propionateFour grams of methyl 3-(1,3-dimethoxy-9-oxo-4-acridanyl)-propionate,prepared as in Example 4, were dissolved in 300 ml. of methylenechloride and the solution treated with an excess of gaseous borontrichloride at a temperature of 5 C. The reaction mixture was thenallowed to remain at room temperature for 30 minutes after which time300 ml. of water were added. The methylene chloride layer containingmethyl 3-(l-hydroxy-3- Inethoxy-9 oxo 4 acridanyl)-propionate formed inthe above reaction was separated and washed successively with 300 ml.water, 300 ml. of a saturated solution of sodium chloride. The washedmethylene chloride layer was dried and the solvent evaporated therefromyielding as a residue 3 g. of methyl 3-(1-hydroxy-3-methoxy-9-oxo-4-acidanyl)-propionate melting at about 194-195 C. afterrecrystallization from a chloroform-ethyl alcohol solvent mixture.

Analysis.Calculated (percent): C, 66.05; H, 5.24; N, 4.28. Found(percent): C, 65.91; H, 5.67; N, 3.94.

8 EXAMPLE 6 Methyl 3-(1-hydroxy-3-methoxy-9-o-xo-4-acridany1) propionate(Grignard method) To an ethereal solution of methylmagnesium iodideprepared in the usual manner from 200 mg. of magnesium and 0.3 ml. ofmethyl iodide, 10 ml. of dry pyridine were carefully added followed bymg. of methyl 3- (1,3 dimethoxy-9-oxo-4-acridanyl)-propionate dissolvedin 15 ml. of pyridine. The reaction mixture was heated at a temperatureof about 50 C. to about 60 C. for 20 hours and then poured over anice-water mixture. The methyl 3-'(1-hydroxy-3-methoxy-9-oxo-4-acridanyl)-propionate formed in the abovereaction was extracted into chloroform, and the extract separated andwashed with a saturated solution of ammonium chloride. The organic layerwas then dried and the solvent evaporated therefrom in vacuo. 144.2milligrams of methyl 3-(1-hydroxy-3-methoxy-9-oxo-4-acridanyl)-propionate were obtained, melting at about194195 C. after recrystallization from aqueous methanol.

EXAMPLE 7 1-hydroxy-4- (3-hydroxy-3-methylbutyl)-3- methoxy-9-acridanoneSix hundred fifty milligrams of methyl 3-(1-hydroxy-3-methoxy-9-0xo-4-acridanyl)-propionate, prepared as in Example 5, weredissolved in 50 ml. of tetrahydrofuran and reacted with 10 ml. of a 1.7molar solution of methyllithium in diethyl ether at a temperature of -l9C. The above reaction was carried out under nitrogen with continualstirring. After about 30 minutes, the reaction mixture was decomposedwith 100 ml. of 3 N hydrochloric acid and the1-hydroxy-4-(3-hydroxy-3-methylbutyl)-3- methoxy-9-acridanone formed inthe above reaction was extracted therefrom with 200 ml. of ethylacetate. The extract was washed successively with 200 ml. of a saturatedsolution of sodium chloride, 200 ml. of a saturated solution of sodiumcarbonate and again with a saturated solution of sodium chloride. Theextract was dried and the solvent evaporated therefrom. 683 milligramsof lhydroxy-4-(3 hydroxy-3-methyl-butyl) 3 methoxy-9- oxoacridanone wereobtained melting at about 213214 C. after recrystallization from ethylacetate.

Analysis.Calculated (percent): C, 69.70; H, 6.47; N, 4.28. Found(percent): C, 69.41; H, 6.44; N, 4.27.

EXAMPLE 8 6-hydroxy-3,3-dimethyl-2,3-dihydro-7(12H)-1H- pyrano [2,3-c]acridinone Nine hundred eighty-five milligrams of 1-hydroxy-4- (3hydroxy 3 methylbutyl) 3-methoxy-9-acridanone, prepared as in Example 7,were heated with 25 g. of pyridine hydrochloride at a temperature of toC. for 3 hours. The product of the reaction, 6-hydroxy-3,3- dimethyl 2,3dihydro 7(12H) 1H-pyrano[2,3-c] acridinone, crystallized from thereaction mixture on the addition of 200 ml. of water and was collectedby filtration. The compound was purified by chromatography, using a 5:1benzene-ethyl acetate eluant over a column packed with 60 g. of silicagel. Thirty-five fractions of 22 ml. each were collected at a flow rateof 88 ml. per hour. Fractions 15 to 29 were combined and evaporated invacuo, and the solid residue recrystallized from a chloroform-ethanolsolvent mixture to yield 84 mg. of purified 6 hydroxy 3,3 dimethyl 2,3dihydro 7(12H)-1H- pyrano[2,3-c]acridinone melting at about 273 274 C.

Analysis.-Calculated (percent): C, 73.20; H, 5.80; N, 4.74. Found(percent): C, 73.38; H, 5.65; N, 4.56.

EXAMPLE 9 Nordihydroacronycine Forty-seven milligrams of 6 hydroxy 3,3dimethyl- 2,3 dihydro 7(12H) 1H pyrano[2,3-c]acridinone,

prepared as in Example 8, were dissolved in 50 ml. of acetone andreacted with ml. of methyl iodide at reflux temperature for 5 hours inthe presence of 4 g. of potassium carbonate. The reaction mixture wasfiltered and then diluted with 100 ml. of water. The acetone was removedby evaporation and nordihydroacronycine, formed in the above reaction,was extracted from the aqueous layer with 100 ml. 'of ethyl acetate. Theextract was washed with 100 ml. of a saturated solution of sodiumchloride, dried, and the ethyl acetate removed therefrom by evaporationin vacuo. 19.7 milligrams of nordihydroacronycine were obtained, meltingat about 205 212 C. after recrystallization from chloroform-ethanol.

Analysis.Calculated (percent): C, 73.77; H, 6.19; N, 4.53. Found(percent): C, 73.61; H, 6.11; N, 4.53.

EXAMPLE Noracronycine 309.4 milligrams of nordihydroacronycine, preparedas in Example 9, and 249.7 mg. of 2,3-dichloro-5,S-dicyanoquinone werereacted in 125 ml. of toluene at reflux temperature for 1.5 hours. Thereaction mixture was cooled to room temperature, and diluted with 125ml. of ethyl acetate. The diluted reaction mixture, after being washedsuccessively with 250 ml. of a 5% solution of sodium hydroxide and with250 ml. of a saturated solution of sodium chloride, was dried and thesolvent evaporated in vacuo to yield 300 mg. of a solid residuecontaining noracronycine. The noracronycine was purified bychromatography using a :1 benzene-ethyl acetate eluant, over a columnpacked with 200 g. of silica gel. One hundred and forty fractions werecollected of 15 ml. each. Fractions 84 to 103 were combined andevaporated in vacuo to yield 144 mg. of noracronycine melting at about200 to 200.5 C. after recrystallization from ethyl acetate.

EXAMPLE l1 6-hydroxy-3,3-diethyl-10-nitro-2,3-dihydro-7(12H)- lH-pyrano[2,3-c] acridinone Following the procedure of Example 1, 3,5di-npropoxy-n-fi-chloropropionylaniline can be fused in the presence ofstannous chloride and sodium chloride to yield5,7-di-n-propoxy-3,4-dihydrocarbostyril. Reaction of this compound with4 nitro 2 iodobenzoic acid under Ullmann conditions yields 1 (2 carboxy5 nitrophenyl) 5,7 di-n-propoxy 3,4 dihydrocarbostyril. Treatment ofthis latter compound with polyphosphoric acid followed by esterificationof the resulting product with ethanolic hydrogen chloride gives ethyl3-(1,3-di-n-propoxy 6 nitro 9 oxo 4 acridanyl)-propionate, selectivede-etherification of which yields the corresponding l-hydroxyderivative. Reaction of this latter compound with ethyllithium gives 1hydroxy 4 (3-hydroxy-3-6-hydroxy-3,3-di-n-propyl-10-chloro-2,3-dihydro-7 12H) 1H-pyrano[2,3 -c]acridinone 6-hydroxy-3 ,3diisobutyl-8-methyl-2,3-dihydro-7 12H)lH-pyrano [2,3 -c] acridin one6-hydroxy-3,3-di-n-butyl-8-trifluoromethyl-2,3-dihydro- 7 12H)-1H-pyrano [2, 3-c] acridinone6-hydroxy-3,3-di-ethyl-9-ethoxy-2,3-dihydro-7 12H lH-pyrano [2,3-c]acridinone I claim:

1. The compound of the formula 0-CHa \N -0-CH3 wherein R" is methyl orethyl.

2. The compound of the formula 0 O H A Til: Hg-CHz-C O 0 R" wherein R"is methyl or ethyl.

3. The compound of the formula References Cited Beck et al.: Jour. Am.Chem. Soc., vol. 89, p. 3934 (1967).

DONALD G. DAUS, Primary Examiner

